Abstract 21305: Sustained Sildenafil Treatment Improves Left Ventricular Function and Attenuates Adverse Remodeling One Year After Myocardial Infarction in Mice.
Background: Phosphodiesterase-5 (PDE5) inhibitors reduce infarct size and protect against early LV dysfunction after myocardial infarction (MI) in mice. The effect of sustained administration of PDE5-inhibitors on long-term survival and development of heart failure after MI has not been studied.
Methods: Ten weeks after MI, induced by permanent LAD ligation, mice (n=53) were randomized to receive the PDE5-specific inhibitor sildenafil, (SIL 100 mg/kg/day via drinking water) or placebo. After 1 year, LV function and remodeling were measured using cine-MRI (9.4T Bruker) and invasive pressure-volume (P-V) catheterization. Heart weight normalized to tibia length (HW/TL) and cardiomyocyte (CM) width in the MI border zone were measured. In addition, we investigated the effect of SIL on LV remodeling in mice with overexpression of PDE5 in cardiac myocytes (PDE5TG, n=53).
Results: Survival at 1y was 34% in placebo but markedly greater following SIL (50%). SIL attenuated global LV dysfunction measured using MRI (LVEF 24±7 %, n=13 vs 19±5 % in placebo, n=7, p=0.08). Hemodynamic measurements indicated that SIL increased LVEF (P<0.05), an effect attributable to a reduction in end-systolic volume (22±7 vs 28±4 µl without SIL, P<0.05) and an increase in preload recruitable stroke work, a load-independent index of systolic function (58±17 vs 35±7 mmHg without SIL, P<0.05). In PDE5TG, survival at 1y was 30% but again markedly greater following SIL (62%). MRI-derived LVEF was similarly reduced to 19±5 % (n=10) and P-V analysis revealed that systolic dysfunction was accompanied by accentuated LV dilatation. SIL increased LVEF (29±12%, n=14, P<0.05 vs no SIL), and reduced end-diastolic and end-systolic volumes (32±7 vs 42±9µl and 24±7 vs 33±8µl without SIL, respectively, P<0.05 for both). HW/TL ratio was significantly reduced after SIL (10.3±2.9 vs 13.1±3.9 mg/mm in PDE5TG, P<0.05), an effect associated with a modest reduction in CM width.
Conclusion: Long-term sildenafil treatment prevents deterioration of LV function and adverse remodeling in mice after MI. In mice over-expressing PDE5 in cardiac myocytes, the SIL-inhibitable adverse LV remodeling at 1 year was markedly accentuated. Inhibition of PDE5 may be an attractive strategy to prevent heart failure after MI.
- © 2010 by American Heart Association, Inc.